The present invention relates to 7-N,8-N-ethylenemitomycin 8-imines having an antitumor activity.
Mitomycins are generally known to be antibiotics having an antitumor activity. From the natural source, mitomycin C is mainly obtained, and as trace components, mitomycins A and B and porfiromycin (these are described in Merck Index, 10th edition) are obtained. Further, as trace components, mitomycins D and E as disclosed in Japanese Published Unexamined Patent Application No. 122797/79, mitomycins F and J as disclosed in Japanese Published Unexamined Patent Application No. 45322/80, mitomycins G, H and K as disclosed in Japanese Published Unexamined Patent Application No. 118396/80 and the like are also known. Structures of these mitomycins obtained from the natural source are shown in Table 1.
In addition, using the mitomycins described above as starting materials, mitomycins which are not available from the natural source are synthesized, and 9a-O-demethylmitomycin G as disclosed in Japanese Published Unexamined Patent Application No. 15408/80, 1a-demethylmitomycins G and K as disclosed in Japanese Published Unexamined Patent Application No. 7787/81, 9-epi-mitomycins B and D as disclosed in Japanese Published Unexamined Patent Application No. 30978/81 and the like are known. Structures of these mitomycins are shown in Table 2.
TABLE 1 __________________________________________________________________________ Structures of Mitomycins obtained from the Natural Source ##STR2## Mitomycin X.sub.A Y.sub.A Z.sub.A R.sub.A R.sub.B __________________________________________________________________________ A OCH.sub.3 CH.sub.3 H CH.sub.2 OCONH.sub.2 H B OCH.sub.3 H CH.sub.3 H CH.sub.2 OCONH.sub.2 C NH.sub.2 CH.sub.3 H CH.sub.2 OCONH.sub.2 H D NH.sub.2 H CH.sub.3 H CH.sub.2 OCONH.sub.2 E NH.sub.2 CH.sub.3 CH.sub.3 H CH.sub.2 OCONH.sub.2 F OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 OCONH.sub.2 H Combined together G NH.sub.2 CH.sub.3 CH.sub.3 to form CH.sub.2 Combined together H OCH.sub.3 H CH.sub.3 to form CH.sub.2 J OCH.sub.3 CH.sub.3 CH.sub.3 H CH.sub.2 OCONH.sub.2 Combined together K OCH.sub.3 CH.sub.3 CH.sub.3 to form CH.sub.2 Porfiromycin NH.sub.2 CH.sub.3 CH.sub.3 CH.sub.2 OCONH.sub.2 H __________________________________________________________________________
TABLE 2 ______________________________________ Structures of Non-naturally Occurring Mitomycins ##STR3## Mitomycin X.sub.A Y.sub.A Z.sub.A R.sub.A R.sub.B ______________________________________ 9a-ODemethyl NH.sub.2 H CH.sub.3 Combined together mitomycin G to form CH.sub.2 1a-Demethyl NH.sub.2 CH.sub.3 H Combined together mitomycin G to form CH.sub.2 1a-Demethyl OCH.sub.3 CH.sub.3 H Combined together mitomycin K to form CH.sub.2 9-Epi-mitomy- OCH.sub.3 H CH.sub.3 CH.sub.2 OCONH.sub.2 H cin B 9-Epi-mitomy- NH.sub.2 H CH.sub.3 CH.sub.2 OCONH.sub.2 H cin D ______________________________________
As compounds containing a 2-aminoethyl group at the 7-amino group, 7-N-(2-dimethylaminoethyl)mitomycin C as disclosed in Japanese Published Unexamined Patent Application No. 188590/82 and Journal of Medicinal Chemistry, 26, 16-20 (1983), 7-N-methyl-7-N-(2-methylaminoethyl)mitomycin C as disclosed in Japanese Published Unexamined Patent Application No. 152384/84, 7-N-methyl-7-N-(2-dimethylaminoethyl)mitomycin C as disclosed in Journal of Medicinal Chemistry, 26, 1453-1457 (1983), 7-N-(2-aminoethyl)mitomycin C as disclosed in Journal of Medicinal Chemistry, 26, 16-20 (1983) (hereinafter referred to as Publication A) and Japanese Published Unexamined Patent Application No. 152384/84, etc. are mentioned. Among these mitomycins mentioned above, 7-N-(2-aminoethyl)mitomycin C is particularly relevant to the compound of the present invention. 7-N-(2-aminoethyl)mitomycin C is reported as Compound 13 in Publication A and as the compound illustrated in Example 22 of Japanese Published Unexamined Patent Application No. 152384/84.
According to Publication A, 7-N-(2-aminoethyl)mitomycin C is reported as the compound having the following physicochemical properties: melting point (202 to 205.degree. C., decomposed), elemental analysis (carbon: found, 47.41%; calculated as C.sub.17 H.sub.23 N.sub.5 O.sub.5.CH.sub.2 Cl.sub.2, 46.76%) and NMR [as signals derived from the 7-substituent (H.sub.2 NCH.sub.2 CH.sub.2 NH-) in CDCl.sub.3, .delta.1.47 (brs, 2H), 3.50 (brs, 2H)]. From these data, however, it is difficult to positively support the structure of 7-N-(2-aminoethyl)mitomycin C. Based on physicochemical data given in Reference Example 1 of the present specification, especially MS, NMR spectrum, etc. which reflect the molecular formula, the structure of the compound as disclosed in Publication A should be corrected to be 7-N,8-N-ethylenemitomycin 8-imine (hereinafter referred to as Compound A).
As clear from the foregoing publications, Compound A and various mitomycins are known. However, even Compound A does not reach a satisfactory level of potency of antitumor activity and reduction in toxicity, and the development of better antitumor agents has been desired.